D'Souza Sudhir Jude Anthony, Vespa Alisa, Murkherjee Suranjana, Maher Amy, Pajak Agnieszka, Dagnino Lina
Department of Pharmacology, Child Health Research Institute, University of Western Ontario, London, Ontario N6A 5C1, Canada.
J Biol Chem. 2002 Mar 22;277(12):10626-32. doi: 10.1074/jbc.M111956200. Epub 2002 Jan 14.
E2F factors are involved in proliferation and apoptosis. To understand the role of E2F-1 in the epidermis, we screened wild type and E2F-1(-/-) keratinocyte mRNA for genes differentially expressed in the two cell populations. We demonstrate the reduced expression of integrins alpha(5), alpha(6), beta(1), and beta(4) in E2F-1(-/-) keratinocytes associated with reduced activation of Jun terminal kinase and Erk upon integrin stimulation. As a consequence of altered integrin expression and function, E2F-1(-/-) keratinocytes also show impaired migration, adhesion to extracellular matrix proteins, and a blunted chemotactic response to transforming growth factor-gamma1. E2F-1(-/-) keratinocytes, but not dermal fibroblasts, exhibit altered patterns of proliferation, including significant delays in transit through both G(1) and S phases of the cell cycle. Recognizing that proliferation and migration are key for proper wound healing in vivo, we postulated that E2F-1(-/-) mice may exhibit abnormal epidermal repair upon injury. Consistent with our hypothesis, E2F-1(-/-) mice exhibited impaired cutaneous wound healing. This defect is associated with substantially reduced local inflammatory responses and rates of re-epithelialization. Thus, we demonstrate that E2F-1 is indispensable for a hitherto unidentified cell type-specific and unique role in keratinocyte proliferation, adhesion, and migration as well as in proper wound repair and epidermal regeneration in vivo.
E2F 因子参与细胞增殖和凋亡过程。为了解 E2F-1 在表皮中的作用,我们筛选了野生型和 E2F-1(-/-)角质形成细胞的 mRNA,以寻找在这两种细胞群体中差异表达的基因。我们发现,在 E2F-1(-/-)角质形成细胞中,整合素α(5)、α(6)、β(1)和β(4)的表达降低,这与整合素刺激后 Jun 末端激酶和 Erk 的激活减少有关。由于整合素表达和功能的改变,E2F-1(-/-)角质形成细胞还表现出迁移受损、对细胞外基质蛋白的粘附能力下降以及对转化生长因子-γ1 的趋化反应减弱。E2F-1(-/-)角质形成细胞而非真皮成纤维细胞,呈现出改变的增殖模式,包括在细胞周期的 G(1)期和 S 期都有明显延迟。鉴于增殖和迁移是体内伤口正常愈合的关键,我们推测 E2F-1(-/-)小鼠在受伤后可能表现出异常的表皮修复。与我们的假设一致,E2F-1(-/-)小鼠表现出皮肤伤口愈合受损。这种缺陷与局部炎症反应显著减少以及再上皮化速率降低有关。因此,我们证明 E2F-1 对于角质形成细胞增殖、粘附和迁移以及体内正常伤口修复和表皮再生中一种迄今未明确的细胞类型特异性独特作用是不可或缺的。